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Abstract

Introduction

We aimed to explore the associations between knee osteoarthritis (OA)-related tissue
abnormalities assessed by conventional radiography (CR) and by high-resolution 3.0
Tesla magnetic resonance imaging (MRI), as well as biomechanical factors and findings
from physical examination in patients with knee OA.

Results

Quadriceps weakness was associated with cartilage integrity, effusion, synovitis (all
detected by MRI) and CR-detected joint space narrowing. Knee joint laxity was associated
with MRI-detected cartilage integrity, CR-detected joint space narrowing and osteophyte
formation. Multiple tissue abnormalities including cartilage integrity, osteophytes
and effusion, but only those detected by MRI, were found to be associated with physical
examination findings such as crepitus.

Conclusion

We observed clinically relevant findings, including a significant association between
quadriceps weakness and both effusion and synovitis, detected by MRI. Inflammation
was detected in over one-third of the participants, emphasizing the inflammatory component
of OA and a possible important role for anti-inflammatory therapies in knee OA. In
general, OA-related tissue abnormalities of the knee, even those detected by MRI,
were found to be discordant with biomechanical and physical examination features.

Introduction

Osteoarthritis (OA) of the knee involves many tissues of the knee joint, not only
addressing cartilage but also including abnormalities in subchondral bone and the
synovial membrane [1,2]. Most people with knee OA suffer from pain, stiffness and limitations in daily activities
[2]. Physical examination may reveal clinical signs such as joint crepitus, swelling,
deformities or increased warmth of the joint [2]. Additionally, biomechanical factors such as lower limb muscle strength, proprioceptive
accuracy of the knee joint and varus-valgus knee joint laxity, which are considered
essential factors for knee stabilization [3-5], have frequently been found to be impaired in knee OA patients [6-8]. Besides being clinically important consequences of OA, biomechanical factors may
also play a role in the onset of tissue abnormalities [9-12]. Presumably, biomechanical factors in the knee joint and tissue abnormalities interact
with each other during the disease process of OA.

Conventional radiography (CR) is the primary modality for disease diagnosis and classification
in clinical practice [13]. CR-based joint space width (JSW), an indirect measure for cartilage loss, is the
most important outcome measure in pharmacological studies [14]. In contrast to radiography, magnetic resonance imaging (MRI) is able to visualize
cartilage and to detect bone marrow lesions (BML) and inflammation (for example, effusion
and synovitis) [14]. MRI is therefore currently the best modality available for imaging OA-related tissue
abnormalities [14] and may be able to unravel mechanisms underlying biomechanical impairments.

Only a few studies have been performed on the association between tissue abnormalities
and biomechanical factors. While studies using CR provided mixed results [15-19], studies using MRI clearly demonstrated an association between (medial tibiofemoral
and patellafemoral compartmental) cartilage thickness and quadriceps strength [18,20,21]. A small number of studies (using CR or MRI) provided mixed results on the relationship
between tissue abnormalities (namely, cartilage thickness [8,22,23] and osteophyte formation [22,24]) and knee joint laxity, while proprioceptive accuracy and hamstrings muscles have
never been studied in relation to tissue abnormalities.

Most studies concerning OA-related tissue abnormalities focused on the association
with patient-reported pain or activity limitations, generally providing evidence for
discordance - particularly in studies using CR [13,25-32]. OA-related tissue abnormalities are possibly more closely linked to findings from
physical examination, rather than to self-reported outcomes. Recently, a population-based
study using MRI showed that multiple tissue abnormalities were related to the presence
of crepitus [33]. As far as we know, tissue abnormalities have not so far been related to findings
from physical examination in a knee OA population.

In conclusion, there is limited knowledge on the association between OA-related tissue
abnormalities, biomechanical factors and physical examination findings in knee OA.
The first aim of the present study was therefore to explore associations of CR-detected
and MRI-detected tissue abnormalities and biomechanical factors (quadriceps and hamstrings
muscle strength, proprioceptive accuracy and knee joint laxity) in patients with knee
OA. The second aim was to explore associations of CR-detected and MRI-detected tissue
abnormalities and physical examination findings (bony tenderness, crepitus, bony enlargement
and palpable warmth) in patients with knee OA.

Materials and methods

Subjects

For the present study, participants were recruited from a randomized controlled trial
on the effectiveness of a knee stabilization exercise program [34]. Inclusion criteria were clinical knee OA diagnosis according to the American College
of Rheumatology criteria (that is, presence of knee pain and at least three of the
following six items: age >50 years, morning stiffness <30 minutes, crepitus, bony
tenderness, bony enlargement and no palpable warmth) [35], age between 40 and 75 years, instability of the knee and written informed consent.
Total knee arthroplasty, rheumatoid arthritis or any other form of arthritis (that
is, crystal arthropathy, septic arthritis, spondylarthropathy), comorbidities affecting
daily functioning, severe knee pain (numeric rating scale >8) and/or contraindication
for MRI (for example, pacemaker, claustrophobia) were exclusion criteria. Patients
were subsequently examined by radiologists, rheumatologists, and physiatrists. The
measurement protocol contained assessment of demographic, biomechanical and clinical
factors related to OA, as well as CR and MRI, all assessed prior to the start of the
trial. All participants provided written informed consent. The study was approved
by the Reade/Slotervaart Institutional Review Board.

Index knee

For knee-specific variables we used data from the index knee. For unilateral knee
OA patients, the index knee was the knee that was diagnosed with clinical OA. For
bilateral knee OA patients, the index knee was the knee that most severely affected
daily activities on patient self-report.

Biomechanical factors

Measurements of lower limb muscle strength, proprioceptive accuracy and varus-valgus
laxity have been extensively described in previous publications [5,36,37]. In summary, muscle strength was measured isokinetically (60°/second) for both knee
extension (quadriceps) and flexion (hamstrings) strength. Strength outcomes (in Nm)
were adjusted for bodyweight [36]. For proprioceptive accuracy (knee joint motion sense), a threshold detection task
was used - which assessed the amount of degrees after motion detection, with motion
velocity of 0.3°/second [36]. Varus-valgus knee joint laxity was measured as the total range of knee motion (in
degrees) in the frontal plane. In a sitting position, the thigh and lower leg were
fixed at five places to prevent for medial or lateral movement of the thigh and lower
leg and for hip rotation. In a fixed knee flexion of 20°, a load of 1.12 kg (7.7 Nm)
was applied to the lower leg both medially and laterally, resulting in varus or valgus
movement across the transverse axis of the knee joint [37].

Physical examination findings

The following features from the American College of Rheumatology criteria for clinical
knee OA diagnosis were assessed by the physiatrist on physical examination of the
knee joint: bony tenderness (that is, pain by palpation at the joint line), crepitus
(that is, crackling or grinding sound in the joint during weight bearing), bony enlargement
at joint line and palpable warmth of the knee joint [35]. Findings were scored as yes (present) or no (absent).

Radiography

Conventional radiographs of tibiofemoral joints were made by a weight-bearing posterioanterior
view, semi-flexed (7 to 10°) according to Buckland-Wright and colleagues [38]. Radiographs of patellofemoral joints were made by a single standing mediolateral
view in 30° flexion, and a skyline (inferior superior) view in 30° flexion [39]. Two independent observers (DR, MvdE) graded radiographs, unaware of the patient's
clinical characteristics. One observer (DR) was a bone and joint radiologist, and
the second observer (MvdE) was an epidemiologist trained by two musculoskeletal radiologists.
The JSW and osteophyte formation were scored on a scale of 0 to 3, for medial tibiofemoral
(MTF), lateral tibiofemoral (LTF) and patellafemoral (PF) compartments separately,
according to the Osteoarthritis Research Society International (OARSI) atlas [40]. Severity of structural damage in the knee, according to Kellgren-Lawrence [41], was also scored. The intraclass correlation coefficient for interrater reliability
in 64 knees was 0.87 (P <0.001) for JSW, 0.60 (P <0.001) for osteophytes and 0.89 (P <0.001) for the Kellgren-Lawrence score.

MRI scans were assessed according to the Boston-Leeds Osteoarthritis Knee Score system
[42], a semi-quantitative whole-joint scoring method. A radiologist (J-PK) with 27 years
of musculoskeletal expertise, blinded to the patient's clinical characteristics and
radiographic assessment, assessed all MRI scans. Cartilage integrity, osteophyte formation
and BML were scored per region, with scores ranging from 0 (no abnormality) to 3 (severe
abnormality). For effusion, one knee-specific score was used, ranging from 0 (physiological
amount of effusion) to 3 (large effusion). Presence of synovitis (yes/no) was assessed
in five regions separately. Specific details on MRI assessment are presented in Table
1. The intraclass correlation coefficient for intrarater reliability in 15 knees was
found to be 0.83 (P <0.001) for cartilage thickness, 0.86 (P <0.001) for osteophytes, 0.91 (P <0.001) for BML, and 0.97 (P <0.001) for effusion. Cohen's kappa for synovitis was 0.73 (P = 0.003).

Statistical analysis

Firstly, descriptive statistics were calculated. Secondly, linear and logistic regression
analyses were performed for associations of tissue abnormalities (independent variables)
with biomechanical factors and physical examination findings (dependent variables),
for continuous and dichotomous scales respectively. Compartment-specific scores for
JSW and osteophytes, detected by CR, were dichotomized by combining scores 0 and 1
(that is, only minute abnormality) and combining scores 2 and 3 (that is, at least
definite abnormality) for each compartment separately. Region-specific scores (0 to
3) for cartilage integrity, osteophytes and BML, detected by MRI, were summed into
compartment-specific scores [27,43-45]. Knee-specific scores for MRI-based effusion were dichotomized, by combining scores
0 and 1 (physiological amount/small effusion) and by combining scores 2 and 3 (medium/large
effusion) [28,46]. Region-specific scores for MRI-based synovitis were also dichotomized into one knee-specific
score (no synovitis at all vs. synovitis present in at least one region). Regression
analyses were performed univariably as well as multivariably with adjustment for age,
gender and duration of knee symptoms. Standardized regression β coefficients and P values were estimated for linear regression analyses; odds ratios and P values were estimated for logistic regression analyses. Statistical significance was
accepted at P <0.05. All analyses were performed using PASW Statistics 18.0 (SPSS Inc., Chicago,
IL, USA).

Results

From a total of 112 potential candidates that participated in a randomized controlled
trial [34] from January 2010, seven persons were excluded (because MRI could not be scheduled
before the start of the trial). Patient characteristics of the study sample (n = 105) are presented in Table 2. In general, study participants demonstrated multiple severe tissue abnormalities,
detected by both CR and MRI, indicating an advanced OA group. An overview of all study
findings is presented in Table 3.

No associations were found between features from CR and findings from physical examination,
as shown in Table 5. On the contrary, multiple MRI features (that is, LTF cartilage integrity, osteophytes
in MTF, LTF and PF compartments and effusion) were found to be significantly associated
with crepitus, while the association with MTF cartilage integrity was of borderline
significance (P = 0.050).

Discussion

This is the first knee OA study exploring associations between multiple tissue abnormalities,
biomechanical factors and physical examination findings. The study provided several
clinically relevant findings. Firstly, the clinically relevant and new finding that
high-resolution 3.0 Tesla MRI-detected effusion and synovitis, associated with quadriceps
weakness. Secondly, several tissue abnormalities (that is, cartilage integrity, osteophytes
and effusion), but only when detected by MRI, were found to be associated with the
presence of crepitus. Thirdly, we found associations of cartilage integrity with quadriceps
weakness and reduced varus-valgus laxity.

The present explorative study showed only a limited amount of significant associations,
which indicates discordance between tissue abnormalities and clinical features in
knee OA patients. The lack of significant associations between radiographic and clinical
features is not surprising, as the discordance between radiographic and clinical OA
[13] is well known and, at least partly, related to the heterogeneity of OA. However,
since pain severity has been found to be more closely linked to MRI features than
to CR features [47], we were surprised by the limited amount of significant associations between MRI
features, biomechanical factors and physical examination findings.

High-resolution MRI and CR provided similar patterns of association. Firstly, reduced
PF cartilage integrity, both MRI based and CR based, was associated with quadriceps
weakness, which confirms previous studies [18,20,21]. Secondly, MRI-based and CR-based MTF cartilage integrity loss was related to lower
varus-valgus laxity. Although these associations were weak and inconsistent with previous
studies [8,22,23], they might be indicative for an ankylosing effect of end-stage cartilage integrity
(that is, reduced joint motion due to bone-to-bone) [48]. Others suggested that cartilage loss results in higher laxity due to reduced tension
on ligaments (pseudo-laxity [8]), which might underlie our finding of reduced LTF cartilage integrity (but only on
CR) associated with higher laxity. Future studies are needed to clarify the association
between cartilage integrity and laxity. Thirdly, neither features from MRI nor from
CR were significantly related to hamstrings strength and proprioceptive accuracy.
Finally, no associations were found between tissue abnormalities (MRI and CR) and
physical examination findings (except for crepitus), which might, at least partly,
be explained by the low proportion of persons with bony enlargement (11%) or palpable
warmth (4%) in our cohort. These similar patterns of findings from CR and MRI were
determined in a study sample of patients with advanced knee OA with knee complaints
for more than 10 years on average. Since MRI is able to detect tissue abnormalities
at a much earlier stage of the disease than CR [31], a different pattern of associations with clinical features may possibly be found
in an early OA sample. On the other hand, two results from our study may be indicative
for an additional value of MRI over CR. Firstly, MRI-based effusion and synovitis,
which cannot be detected by CR, were found to be significantly associated with quadriceps
weakness. Secondly, crepitus of the knee was associated with multiple MRI features
(that is, LTF cartilage integrity, osteophytes in all three compartments and effusion),
similar to a recently conducted population-based study [33], but was not associated with any feature from CR. This indicates that MRI seems to
be able to visualize features underlying crepitus, while CR is not.

A new and potentially important finding from our study is the association of OA-related
inflammation (effusion and/or synovitis) with quadriceps weakness, which is in line
with previous experimental studies demonstrating an effect of effusion on quadriceps
function [49-51]. Quadriceps muscles are considered the most important muscles for knee movements,
stabilization and shock absorption [11]. Persons with synovitis and/or effusion had significantly lower quadriceps strength
compared with persons without synovitis/effusion. In secondary analyses, similar results
were yielded after adjustment for pain severity, indicating that pain does not explain
the association between inflammation and quadriceps weakness. Because inflammation
of the synovial membrane had mostly been identified in the infrapatellar region (that
is, in 86% of persons with synovitis), which is adjacent to the patellar tendon of
the quadriceps muscles, it seems plausible that quadriceps function is affected by
inflammatory processes nearby the patella. In addition, inflammation may occur inside
the muscle as well, which could result in decreased muscle strength [52]. Effusion is presumed to cause muscle weakness by muscle reflex inhibition due to
increased intra-articular pressure [49-51]. Although knee joint inflammation has been suggested to also affect proprioceptive
accuracy [7], we were not able to demonstrate this. A possible explanation could be that our study
participants demonstrated relatively healthy proprioceptive accuracy. Previous studies
provided conflicting results for the role of non-inflammatory effusion (that is, saline
injections) in proprioceptive accuracy [53,54]. Future studies need to focus on OA-related inflammation, instead of non-inflammatory
injections, to clarify the role of inflammation in proprioception.

The associations between effusion, synovitis and quadriceps weakness could be highly
relevant for selecting knee OA treatment. If inflammatory processes underlie quadriceps
weakness, regular quadriceps strengthening exercises are not likely to be beneficial
and anti-inflammatory therapy might be needed first. This implication is in line with
a recent study in which patients treated with both NSAIDs and exercises improved more
in muscle strength compared with patients treated with exercises only [55]. In addition, our data revealed that physical examination of the knee strongly underestimated
the prevalence of inflammation of the knee, since warmth was palpated in only 4% of
our participants, compared with a prevalence of 34% for synovitis and 39% for medium/large
effusion, detected by MRI. This implies that MRI may have additional value for clinical
assessment in patients with inflammation. Our findings also emphasize that OA is not
only characterized by cartilage degeneration and bony changes but also by inflammatory
changes, which may point out the importance of anti-inflammatory therapies in knee
OA.

Our study design has some limitations that need to be noticed. Firstly, we did not
use contrast-enhanced MR imaging techniques to minimize risks for participants (for
example, risk of allergic reactions, nephropathy). Because of the well-known superiority
of contrast-enhanced MRI for synovitis detection [56], it is remarkable that even without contrast infusions we were able to detect an
association of both effusion and synovitis with quadriceps weakness. Although noncontrast-enhanced
MRI demonstrated lower specificity for detecting synovitis compared with contrast-enhanced
MRI, meaning that signal intensity alterations do not always represent synovitis,
it is also been found to be a highly sensitive technique (≈100% sensitivity) for synovitis
detection [57]. This implies that the prevalence of synovitis in our study could be an overestimation,
but that all persons with actual synovitis have presumably been detected. Secondly,
we are not sure whether the power of our study was sufficient. Most MRI studies included
large cohorts (n >200), while our study consists of 105 participants. This sample size may have resulted
in loss of statistical power. In addition, participants had been selected based on
the presence of knee joint instability, since they participated in a study on the
effectiveness of a knee stabilization exercise program, which may have introduced
selection bias in the present study. Thirdly, our study design was cross-sectional
with no control group, while a longitudinal design, preferably using a control group
of patients at risk, is necessary to unravel interactions between tissue abnormalities,
biomechanical factors and physical examination findings. However, this study has a
unique design because it is the first study we are aware of in which associations
could be explored between both radiography and MRI with biomechanical and physical
examination features in a knee OA cohort.

Conclusions

This explorative study detected several new and clinically relevant findings, including
associations of MRI-based effusion/synovitis with quadriceps weakness. Inflammation
was detected in over one-third of the participants, emphasizing the inflammatory component
of OA and a possible important role of anti-inflammatory therapies in knee OA. In
general, OA-related tissue abnormalities of the knee, even those detected by MRI,
were found to be discordant with biomechanical and physical examination features.
As this is an explorative study, replication in future research is needed.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

JK, JD and WFL were responsible for conception and design. JK, JD, JPK, MvdL, MvdE,
DR, REV, MG, LDR, MPMS and WFL were responsible for acquisition of data or analysis
and interpretation of data. All authors were responsible for drafting the article
or revising it critically for important intellectual content. All authors read and
approved the manuscript for publication. JK takes full responsibility for the integrity
of the work as a whole, from inception to finished article.

Acknowledgements

The authors gratefully acknowledge T Schweigmann for obtaining MRI scans and S Romviel
for biomechanical and clinical assessments. The study was funded by the Dutch Arthritis
Association and Servier. The study sponsors had no involvement in the study.

References

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